Vitamin D3 was discovered as a result of efforts to determine the nutritive factor responsible for the antirachitic property (i.e., ability to prevent rickets) of cod liver oil. Vitamin D3 (also called cholecalciferol) is photosynthesized from 7-dehydroxycholesterol (previtamin D3) in skin by UV-induced cleavage of the carbon-carbon bond between C9 and C10, enters circulation, and binds to vitamin D binding protein (DBP) for transport. DBP-bound vitamin D3 is biologically inert and requires activation. In the liver vitamin D3 is hydroxylated at the C-25 position by a cytochrome P-450 enzyme system to monohydroxyvitamin D.sub.3, 25(OH)D.sub.3, the major circulating form of vitamin D. This metabolite is hydroxylated again in the kidney at the C-1 position to form dihydroxyvitamin D.sub.3, 1,25(OH).sub.2 D.sub.3, the hormonally active vitamin D metabolite. Dihydroxyvitamin D.sub.3 is metabolized by 24-hydroxylase at the C-24 position to form 1,24,25-trihydroxyvitamin D3 (1,24,25(OH).sub.3 D.sub.3), which is biologically inert. The trihydroxyvitamin D.sub.3 is ultimately metabolized to calcitroic acid. In vitro studies of the metabolism of 1,25(OH).sub.2 D.sub.3 indicate that it catalyzes its own catabolism, but a mechanism therefor has not been suggested. Ray, S., et al., J. Cell Biochem (1995) 59:117-122.
The cellular receptor for 1,25(OH).sub.2 D.sub.3 (designated VDR, for Vitamin D Receptor) is a member of family II of the hormone receptor superfamily of transcription factors. VDR has been fully characterized and is primarily localized in the nuclear compartment of the cell. In the cell nucleus, VDR, in the presence of 1,25(OH).sub.2 D.sub.3, heterodimerizes with the retinoid X receptor (RXR). This dimeric complex binds to a vitamin D responsive element (VDRE, characterized by direct repeats of the hexamer AGGTCA spaced by three nucleotides) and activates vitamin D responsive genes.
9-cis retinoic acid is the native ligand for RXR. Its effect in vivo on the above-described intracellular action of 1,25(OH).sub.2 D.sub.3 is not known.
1,25(OH).sub.2 D.sub.3 's antirachitic activity is based on its enhancement of intestinal absorption of dietary calcium and its mobilization of calcium stores from bone. More recently it has been found to decrease proliferation and increase terminal differentiation of human keratinocytes, and to exhibit immunosuppressive activity on Th.sub.1 cells. These findings have led to its use to treat dermatological disorders such as psoriasis. The use of 1,25(OH).sub.2 D.sub.3 to treat dermatological disorders is tempered, however, by its potent calcemic effects. Those effects have led to the development of 1,25(OH).sub.2 D.sub.3 analogs, such as calcipotriene, that have reduced calcemic effects. Even so, the search continues for ways to improve the therapeutic efficacy of 1,25(OH).sub.2 D.sub.3 and its analogs in dermatology.